Tlie overall goal of this project is to understand liow mutations in genes that encode contractile proteins cause clubfoot in a group of disorders called distal arthrogryposis (DA) syndromes and test whether variants in these genes influence risk for isolated clubfoot (IC). IC is a common birth defect affecting ~5,000 infants (about 1 in 735) born in the U.S. each year. One hypothesized cause of IC is abnormal muscle contractile forces acting in utero to malposition the ankle. However the mechanism by which contractile forces could be altered in the absence of an abnormal neurological exam is unclear. One strategy to discover this mechanism is to find polymorphisms that influence susceptibility to IC. IC is a complex trait that is influenced by several major genes, but to date no polymorphism has been strongly associated with IC risk. Clubfoot in neurologically normal individuals is the major characteristic of DAs. Recently, we have shown that DAs are caused by mutations in at least 7 genes (TNNI2, TNNT3, TPM2, MYH3, MYH8, l\/IYH2, MYH13) that encode contractile proteins expressed in skeletal muscle, and these mutations appear to alter the mechanical properties of reconstituted contractile complexes. We propose to 1) identify and characterize the genetic basis of two new dominantly-inherited DA disorders characterized by foot contractures and IC, 2) determine whether mutations in TNNI2, TNNT3, TPM2, and MYH3 alter the contractile properties of muscles in individuals with DA, and 3) test whether variants in genes that encode contractile proteins found in fast-twitch myofibers influence risk for IC. Identifying risk variants for IC and understanding the mechanism by which mutant contractile proteins affect muscle function will substantially improve our understanding of the pathogenesis of IC, facilitate the development of new diagnostic tests, and provide a basis for exploring novel therapies for IC. My goal is to develop a career as an independent physician-scientist devoted to utilizing translational research techniques to determine the molecular basis of genetic disorders in children. A five year mentored program is proposed that will incorporate both didactic and research training and will be guided by a well-established investigator at the University of Washington. PUBLIC HEALTH RELEVANCE: Isolated clubfoot affects a total of ~100,000 U.S. children <18 years old. The goal of this project is to understand how mutations in genes that encode muscle proteins cause clubfoot in a group of contracture disorders called distal arthrogryposis and test whether variants in these genes influence risk for isolated clubfoot (IC). This knowledge will substantially improve our understanding of the pathogenesis of IC, facilitate the development of new diagnostic tests, and provide a basis for exploring novel therapies for IC.